PGD2/CRTH2在肺动脉高压中的作用及其机制研究

Pulmonary artery narrowness and perivascular inflammation are the pathological hallmark of pulmonary artery hypertension (PAH), T cell-mediated inflammation is involved in progression of PAH. In clinic, elevated urinary prostaglandin (PG) D2 metabolites were observed in the patients with PAH, while its receptor CRTH2 participates Th2 cell infiltration into inflammatory tissues. However, the role of CRTH2 in pathogenesis of PAH remains unknown. We found, deletion of CRTH2 decreased pulmonary artery pressure in hypoxia-induced PAH mouse model, and reduced inflammatory cell infiltration around pulmonary vessels and suppressed the secretion of Th2 cytokines (IL-4 and IL-13), thus we deduce that CRTH2 might mediate the progression of PAH through enhancing Th2 infiltration and secretion of Th2 cytokines. To test our hypothesis, we should further explore the role of CRTH2 in PAH using multiple animal models, examine whether Th2 cell infiltration mediated by CRTH2 receptor is implicated in development of PAH, and finally investigate whether Th2 cytokines (IL-4 and IL-13) promotes pulmonary artery remodeling and analyze the mechanism underlying. Our study will shed light on T cell involvement in PAH development and may identify novel potential target for management of PAH.

肺血管管腔变窄和血管周围炎症是肺动脉高压（PAH）最主要的病理特征，其中T细胞参与了其发生发展。临床上PAH患者尿中前列腺素（PG）D2代谢产物显著增高, 而PGD2的受体CRTH2介导了Th2细胞向炎症组织中浸润，但是CRTH2在PAH中作用仍不清楚。我们前期发现，CRTH2缺失将显著改善小鼠低氧诱导肺动脉高压，减少肺动脉周围炎症细胞浸润，降低血液和肺组织中Th2细胞因子（IL-4和IL-13）分泌。我们推测CRTH2可能通过介导Th2细胞浸润和炎症因子分泌促进PAH进展。为了验证这假设，本研究将利用多种PAH动物模型验证CRTH2在PAH中作用；鉴定CRTH2是否通过调节Th2细胞参与PAH发展；分析CRTH2是否通过IL-4和IL-13促进肺动脉重塑及其分子机制。该研究最终了解Th2细胞参与PAH发展的新机制，并有望找到PAH治疗的潜在靶点

肺动脉平滑肌增生所致的管腔变窄和炎症细胞浸润导致的血管周围炎症是肺动脉高压(PAH)最主要的病理特征。临床上PAH患者尿中前列腺素(PG)D2代谢产物显著增高, 而PGD2的受体CRTH2 介导了Th2细胞向炎症组织中浸润，但是CRTH2在PAH中作用仍不清楚。本课题组前期发现，CRTH2缺失将显著改善小鼠低氧诱导肺动脉高压，减少肺动脉周围炎症细胞浸润，降低血液和肺组织中Th2细胞因子(IL-4和IL-13)分泌。我们推测CRTH2可能通过介导Th2细胞浸润和炎症因子分泌促进PAH进展。在本研究中我们发现CRTH2在特发性肺动脉高压（iPAH）患者和PAH动物模型循环CD3+CD4+T细胞中的表达是上调的。阻断CRTH2可以显著改善PAH小鼠肺动脉的重构和肺动脉压力。CRTH2缺乏会抑制Th2的活化，包括IL-4和IL-13的分泌。CRTH+/+骨髓重建和CRTH+/+CD4+T细胞过继传输都可以使CRTH2-/-PAH小鼠恶化，而在应用IL-4、IL-13双重中和后病情可以出现逆转。抑制CRTH2可以通过抑制Th2的活性来减轻PAH小鼠的病情。体外实验中，Th2细胞中CRTH2的激活可以通过活化STAT6来促进肺动脉平滑肌细胞增殖。综上，本课题组的研究结果表明CRTH2介导的Th2反应在PAH的发生发展过程起到重要作用，这提示我们CRTH2受体可以作为一个潜在的PAH治疗靶点。